Acylated benzylmaltosides as inhibitors of smooth muscle cell proliferation

ABSTRACT

This invention provides smooth muscle cell proliferation inhibitors of formula I having the structure  
                 
wherein 
     R 1 , R 2 , R 3 , R 4 , and R 5  are each, independently, hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R 8 ;    R 6  and R 7  are each, independently, —OH, —OR 9 , O-tert-butyldimethylsilyl, O-trialkylsilyl of 1-6 carbon atoms per alkyl moiety, O-triphenylsilyl,  
                 
   R 8 , R 10 , R 11 , and R 12  are each, independently, hydrogen, —CN, —NO 2 , halogen, CF 3 , alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy of 1-6 carbon atoms;    R 9  is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R 8 ;    Y is O, S, NH, NMe, or CH 2 ;    W is halogen, —CN, CF 3 , alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon atoms, or phenyl mono-, di-, or tri-substituted with R 8 ;    Z is —NO 2 , —NH 2 , —NHR 13 , or —NHCO-Het;    R 13  is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, benzoyl in which the phenyl moiety is substituted with R 8 , or    R 13  is an α-amino acid in which the α carboxyl group forms an amide with the nitrogen of Z, wherein if said amino acid is glutamic acid or aspartic acid, the non-α carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms;    Het is pyridyl substituted with R 8 , thienyl substituted with R 8 , furyl substituted with R 8 , oxazolyl substituted with R 8 , pyrazinyl substituted with R 8 , pyrimidinyl substituted with R 8 , or thiazolyl substituted with R 8 ;    R 14  is R 8 , —NH 2 , —CO 2 H, or —NH-acyl of 2-7 carbon atoms; n=0-3; 
 
with the proviso that when Z is —NHR 13  and Y is O, at least one of R 1 , R 2 , R 3 , R 4 , and R 5  is hydrogen, or at least one of R 6  and R 7  is OH, or a pharmaceutically acceptable salt thereof.

This application claims the benefit of U.S. Provisional Application No.not yet known, which was converted from U.S. patent application Ser. No.09/198,804, filed Nov. 24, 1998, pursuant to a petition filed under 37C.F.R. 1.53(c)(2)(i).

BACKGROUND OF THE INVENTION

This invention relates to the use of substituted acylatedbenzylmaltosides as smooth muscle cell proliferation inhibitors and astherapeutic compositions for treating diseases and conditions which arecharacterized by excessive smooth muscle proliferation such asrestenosis.

All forms of vascular reconstruction such as angioplasty and vein bypassprocedures effect a response to injury that ultimately leads to smoothmuscle cell (SMC) proliferation and subsequently, deposition of profuseamounts of extracellular matrix (Clowes, A. W.; Reidy, M. A. J. Vasc.Surg 1991, 13, 885). These events are also central processes in thepathogenesis of atherosclerosis (Raines E. W.; Ross R. Br. Heart J.1993, 69 (Supplement), S. 30) as well as transplant arteriosclerosis(Isik, F. F.; McDonald, T. O.; Ferguson, M.; Yamanaka, E.; Gordon Am. J.Pathol. 1992, 141, 1139). In the case of restenosis followingangioplasty, clinically relevant solutions for controlling SMCproliferation through pharmacological intervention have remained elusiveto date (Herrman, J. P. R.; Hermans, W. R. M.; Vos, J.; Serruys P. W.Drugs 1993, 4, 18 and 249). Any successful approach to selective SMCproliferation inhibition must not interfere with endothelial cell repairor the normal proliferation and function of other cells (Weissberg, P.L.; Grainger, D. J.; Shanahan C. M.; Metcalfe, J. C. Cardiovascular Res.1993, 27, 1191).

The glycosaminoglycans heparin and heparan sulfate are endogenousinhibitors of SMC proliferation, yet are able to promote endothelialcell growth (Castellot, J. J. Jr.; Wright, T. C.; Karnovsky, M. J.Seminars in Thrombosis and Hemostasis 1987, 13, 489). However, the fullclinical benefits of heparin, heparin fragments, chemically modifiedheparin, low molecular weight heparins, and other heparin mimickinganionic polysaccharides may be compromised due to other pharmacologicalliabilities (excessive bleeding arising from anticoagulation effects, inparticular) coupled with heterogeneity of the various preparations(Borman, S. Chemical and Engineering News, 1993, Jun. 28, 27).

WO 96/14325 discloses acylated benzylglycosides as smooth muscle cellproliferation inhibitors. The compounds of the present invention differin that the substituents on the carbohydrate backbone are different.

Zehavi, U.; Herchman, M. in Carbohyd. Res. 1986, 151, 371, disclosed4-carboxy-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside whichis attached to a polymer for study as an acceptor in the glycogensynthase reaction. The compounds of the present invention differ in thatthe substituents on the benzyl groups are different and the use (smoothmuscle antiproliferation) is different.

Patent numbers U.S. Pat. No. 5,498,775, WO96/14324, and U.S. Pat. No.5,464,827 describe polyanionic benzylglycosides or cyclodextrins assmooth muscle cell proliferation inhibitors for treating diseases andconditions which are characterized by excessive smooth muscleproliferation. β-cyclodextrin tetradecasulfate has been described as asmooth muscle cell proliferation inhibitor and as an effective inhibitorof restenosis (Reilly, C. F.; Fujita, T.; McFall, R. C.; Stabilito, I.I.; Wai-se E.; Johnson, R. G. Drug Development Research 1993, 29, 137).U.S. Pat. No. 5,019,562 discloses anionic derivatives of cyclodextrinsfor treating pathological conditions associated with undesirable cell ortissue growth. WO 93/09790 discloses antiproliferative polyanionicderivatives of cyclodextrins bearing at least 2 anionic residues percarbohydrate residues. Meinetsberger (EP 312087 A2 and EP 312086 A2)describes the antithrombotic and anticoagulant properties of sulfatedbis-aldonic acid amides. U.S. Pat. No. 4,431,637 discloses polysulfatedphenolic glycosides as modulators of the complement system. Thecompounds of the present invention differ from all of the prior art inthat the compounds (a) are benzylmaltosides which bear no structuralresemblance to heparin, sulfated cyclodextrins, or to sulfatedlactobionic acid dimers, (b) contain no more than two contiguous sugarresidues (disaccharide), (c) are of a defined structure, (d) and are notsulfated.

DESCRIPTION OF THE INVENTION

This invention provides benzylmaltosides of formula I

wherein

-   R¹, R², R³, R⁴, and R⁵ are each, independently, hydrogen, acyl of    2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7    carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of    3-8 carbon atoms, or benzoyl in which the phenyl moiety is    substituted with R⁸;-   R⁶ and R⁷ are each, independently, —OH, —OR⁹,    O-tert-butyldimethylsilyl, O-trialkylsilyl of 1-6 carbon atoms per    alkyl moiety, O-triphenylsilyl,-   R⁸, R¹⁰, R¹¹, and R¹² are each, independently, hydrogen, —CN, —NO₂,    halogen, CF₃, alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy    of 1-6 carbon atoms;-   R⁹ is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms,    nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms,    trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the    phenyl moiety is substituted with R⁸;-   Y is O, S, NH, NMe, or CH₂;-   W is halogen, —CN, CF₃, alkyl of 1-6 carbon atoms, haloalkyl of 1-6    carbon atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6    carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon    atoms, or phenyl mono-, di-, or tri-substituted with R⁸;-   Z is —NO₂, —NH₂, —NHR¹³, or —NHCO-Het;-   R¹³ is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms,    nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms,    trifluoromethylacyl of 3-8 carbon atoms, benzoyl in which the phenyl    moiety is substituted with R⁸, or-   R¹³ is an α-amino acid in which the a carboxyl group forms an amide    with the nitrogen of Z, wherein if said amino acid is glutamic acid    or aspartic acid, the non-α carboxylic acid is an alkyl ester in    which the alkyl moiety contains from 1-6 carbon atoms;-   Het is pyridyl substituted with R⁸, thienyl substituted with R⁸,    furyl substituted with R⁸, oxazolyl substituted with R⁸, pyrazinyl    substituted with R⁸, pyrimidinyl substituted with R⁸, or thiazolyl    substituted with R⁸;-   R¹⁴ is R⁸, —NH₂, —CO₂H, or —NH-acyl of 2-7 carbon atoms;-   n=0-3;-   with the proviso that when Z is —NHR¹³ and Y is O, at least one of    R¹, R², R³, R⁴, and R⁵ is hydrogen, or at least one of R⁶ and R⁷ is    OH, or a pharmaceutically acceptable salt thereof.

Alkyl includes both straight chain as well as branched moieties. Halogenmeans bromine, chlorine, fluorine, and iodine. When R¹³ is an α-aminoacid, the carboxyl moiety exists as an amide with the amide nitrogenbeing bonded to the phenyl ring of the compound of formula I. Thefollowing exemplifies the resulting structure when R¹³ is alanine:

When the amino acid contains a second carboxyl moiety, the moiety is analkyl ester of the free acid. The following example shows aspartic acidmethyl ester.

Preferred amino acids include alanine, arginine, aspartic acid, cystine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine, and valine. The amino acids defined by R¹³ include both the Dand L amino acids.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids. Salts may also beformed from organic and inorganic bases, preferably alkali metal salts,for example, sodium, lithium, or potassium. Acid addition salts can beprepared when Y contains a nitrogen or the compound of formula Icontains a basic nitrogen, and base addition salts can typically beprepared when the compound of formula I contains a hydroxyl group.

The compounds of this invention may contain an asymmetric carbon atom orsulfoxide moiety and some of the compounds of this invention may containone or more asymmetric centers and may thus give rise to optical isomersand diastereomers. While shown without respect to stereochemistry inFormula I, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

Preferred compounds of this invention are benzylmaltosides of formula I

wherein

-   R¹, R², R³, R⁴, and R⁵ are each, independently, hydrogen or acyl of    2-7 carbon;-   R⁶ and R⁷ are each, independently, —OH, —OR⁹,    O-tert-butyldimethylsilyl,-   R⁸, R¹⁰, R¹¹, and R¹² are each, independently, hydrogen, —CN, —NO₂,    halogen, CF₃, alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy    of 1-6 carbon atoms;-   R⁹ is acyl of 2-7 carbon atoms, or benzoyl in which the phenyl    moiety is substituted with R⁸;-   Y is O or S;-   W is halogen, or alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon    atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6 carbon    atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon atoms,    or phenyl mono-, di-, or tri-substituted with R⁸;-   Z is —NO₂, —NH₂, —NHR¹³, or —NHCO-Het;-   R¹³ is acyl of 2-7 carbon atoms, or benzoyl in which the phenyl    moiety is substituted with R⁸, or-   R¹³ is an α-amino acid in which the a carboxyl group forms an amide    with the nitrogen of Z, wherein if said amino acid is glutamic acid    or aspartic acid, the non-α carboxylic acid is an alkyl ester in    which the alkyl moiety contains from 1-6 carbon atoms;-   Het is pyridyl substituted with R⁸, thienyl substituted with R⁸,    furyl substituted with R⁸, oxazolyl substituted with R⁸, pyrazinyl    substituted with R⁸, pyrimidinyl substituted with R⁸, or thiazolyl    substituted with R⁸;-   R¹⁴ is R⁸, —NH₂, —CO₂H, or —NH-acyl of 2-7 carbon atoms;-   n=0-3;    with the proviso that when Z is —NHR¹³ and Y is O, at least one of    R¹, R², R³, R⁴, and R⁵ is hydrogen, or at least one of R⁶ and R⁷ is    OH, or a pharmaceutically acceptable salt thereof.

Specifically preferred compounds of this invention are:.

-   4-Chloro-3-nitro-benzyl-β-D-maltoside heptaacetate or a    pharmaceutically acceptable salt thereof;-   N-{5-[(Hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}-L-aspartamidle-γ-tert-butyl    ester or a pharmaceutically acceptable salt thereof;-   N-{2-Chloro-5-[(2,2′,3,3′,4′,6,6′)-hepta-O-acetyl-β-D-maltosyl-oxymethyl]-phenyl}-(9H-fluoren-9-ylmethoxycarbonyl)-L-alaninamide    or a pharmaceutically acceptable salt thereof;-   4-Benzoyl-N-{2-chloro-5-[(2,2′,3,3    ′,4′,6,6′-hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-phenyl}-benzamide    or a pharmaceutically acceptable salt thereof;-   (4-Chloro-3-nitro-benzyl)-hepta-O-acetyl-1-thio-β-D-maltoside or a    pharmaceutically acceptable salt thereof;-   (3-Amino-4-chloro-benzyl) hepta-O-acetyl-1-thio-β-D-maltoside or a    pharmaceutically acceptable salt thereof;-   N-{2-chloro-5-[hepta-O-acetyl-β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamide    or a pharmaceutically acceptable salt thereof;-   5-[(Hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-2-cyano-1-nitrobenzene    or a pharmaceutically acceptable salt thereof.-   N-[2-Chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetantide or a    pharmaceutically acceptable salt thereof;-   N-{5-[6,6′-Di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-2-methyl-phenyl}-acetamide    or a pharmaceutically acceptable salt thereof;-   N-{2-Chloro-5-[6,6′-di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-phenyl}-acetamide    or a pharmaceutically acceptable salt thereof;-   N-{2-Chloro-5-[([6,6′-di-O-benzoyl-β-D-maltosyl]oxy)methyl]phenyl}-acetamide    or a pharmaceutically acceptable salt thereof;-   N-{2-Chloro-5-[([6,6′-di-O-benzoyl-2,2′,3,3′,4′-penta-acetyl-β-D-maltosyl]oxy)-methyl]phenyl}-acetamide    or a pharmaceutically acceptable salt thereof;-   (4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside-6-(3-pyridinecarboxylate)    or a pharmaceutically acceptable salt thereof;-   (4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside    or a pharmaceutically acceptable salt thereof;-   N-[2-Chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)oxy]methyl]phenyl]-3-pyridinecarboxamide    or a pharmaceutically acceptable salt thereof;-   Benzoic acid    6-{4-chloro-3-[(pyridine-3-carbonyl)-amino]-benzyloxy}-4,5-dihydoxy-3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-ylmethyl    ester or a pharmaceutically acceptable salt thereof;-   (4-Chloro-3-nitro-benzyl)-1-deoxy-1-thio-β-D-maltoside or a    pharmaceutically acceptable salt thereof;-   N-{2-chloro-5- [β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamide or a    pharmaceutically acceptable salt thereof;-   5-{[6,6′-Bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene    or a pharmaceutically acceptable salt thereof;-   5-{[2,2′,3,3    ′,4′-Penta-O-acetyl-6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene    or a pharmaceutically acceptable salt thereof;-   5-{[6,6′-Dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-    nitrobenzene or a pharmaceutically acceptable salt thereof; and-   5-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-    oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable    salt thereof.

The compounds of this invention were be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using literature procedures.These schemes show the preparation of representative compounds of thisinvention.

Acetobromomaltose 1 is coupled with a benzyl alcohol 2 in the presenceof a catalyst such as a mercuric bromide, mercuric cyanide, silvertriflate, or silver perchlorate in an aprotic solvent such asacetonitrile, dichloromethane, ether, toluene or nitromethane attemperatures ranging from −40° C. to reflux to yield glycoside 3 (Scheme1). This glycosidation can also be accomplished using Schmidt'strichloroacetimidate coupling with zinc bromide in a solvent such asdichloromethane. Reduction of the nitro group of 3 can be accomplishedwith a reducing agent such as stannous chloride in a polar aproticsolvent such as ethyl acetate at ambient temperature to reflux to affordan anilino compound 4. Coupling of 4 with an acid chloride can becompleted in the presence of an amine base such as triethylamine ordiisopropylethylamine or using a stronger base such as sodium hydride(for sterically hindered systems) in an aprotic solvent such asdichloromethane or tetrahydrofuran at temperatures ranging from 0° C. toambient temperature to yield the target compound 5. The peracetylatedcompound 5 can be converted to the heptahydroxy compound 6 withcatalytic sodium methoxide in methanol or aqueous sodium hydroxide inmethanol at temperatures ranging from ambient temperature to reflux.

As illustrated in Scheme 2, the C-6 and C-6′ positions can beselectively protected as a silyl ether (7) usingt-butyldimethylchlorosilane, a tertiary base such as triethylamine, anda catalytic amount of 4-dimethylaminopyridine. In addition, the 6- and6′-position primary alcohols can be selectively acylated (Scheme 3)using an appropriate acid chloride in a 1:1 mixture of tetrahydrofuranand the hindered base 2,4,6-collidine at −40° C. initially to ambienttemperature overnight. The remaining five secondary alcohols of thedisaccharide can then be protected with acetic anhydride andtriethylarnine in a solvent such as dichloromethane to afford theperacetylated compound 8.

In Scheme 4 the two primary alcohol positions (C-6 and C-6′) are firstconverted to tosylates using tosyl chloride and pyridine in a solventsuch as dichloromethane; the resulting intermediate is thenperacetylated as mentioned above to generate compound 9. Throughdisplacement of the tosylates of 9, heterocyclic ring systems can beincorporated at the 6 and 6′ positions. Finally, the five secondaryacetates are removed with catalytic sodium methoxide in methanol oraqueous sodium hydroxide in methanol at temperatures ranging fromambient temperature to reflux to afford compound 10.

If R₂=OH or OTBDMS:

If R₂=ester linkage:

If R₂=tosylate or inidazole:

The compounds of this invention are useful as antiproliferative agents.The following procedures show the evaluation of representative compoundsof this invention in standard pharmacological test procedure whichmeasured ability of the evaluated compound to inhibit smooth muscle cellproliferation

Effects of Compounds On Cell Proliferation Using ³H ThymidineIncorporation

Human and porcine smooth muscle cells were tested in early passage(generally passage 3-7) at sub-confluent conditions. Cultures were grownin 16 mm (24 well) multi-well culture dishes in medium 199 supplementedwith 10% fetal bovine serum and 2% antibiotic/antimycotic. Atsub-confluence, the cells were placed in a defined serum free medium(AIM-V; Gibco) for 24-48 h prior to initiating the experimentalprotocol.

Although compounds were found to be more effective with longerpre-incubations, in general, the procedures were initiated with theaddition of compound, ³H thymidine and serum/growth factor to serumdeprived synchronized cells and results are reported accordingly.

Compounds were added to each well at 50 fold dilution (20 μL/well) andthe plates were incubated for 24-36 h at 37° C. in 5% CO₂. Compoundswere initially dissolved in 50% ethanol and serially diluted into media.Compounds were routinely evaluated at concentrations from 1 to 100 μM.As a control, grade II porcine intestinal mucosal heparin (sodium salt)was routinely evaluated in all cell preparations at concentrations from0.1 to 100 μg/mL.

At the completion of the test procedure, plates were placed on ice,washed three times with ice cold phosphate buffered saline (PBS) andincubated in ice cold 10% trichloroacetic acid (TCA) got 30 min toremove acid soluble proteins. Solution was transferred to scintillationvials containing 0.4 N HCl (500 μL/vial to neutralize NaOH) and eachwell was rinsed two times with water (500 μL) for a total volume of2mL/vial.

Data was obtained, in triplicate, for both control and experimentalsamples. Control (100%) data was obtained from maximally stimulatedcells, as the result of growth factor or serum stimulation. Experimentaldata was obtained from cells maximally stimulated with growth factor orserum and treated with compound. Data are expressed as an IC₅₀ orpercent inhibition in Table I below. TABLE 1 Porcine Smooth Muscle CellCompound of Example Antiproliferation IC50 1 0.850 μM 2 4.61 μM 3 1.71μM 4 0.164 μM 5 1.14 μM 6 0.667 μM 7 7.97 μM 8 2.05 μM 9 0% @ 500 μM 106.10 μM 11 3.90 μM 12 0.390-2.20 μM 13 0.360 μM 14 6.56 μM 15 73.2 μM 1618% @ 50 μM 17 0.245 μM 18 25% @ 50 μM 19 28% @ 50 μM 20 0.740 μM 2167.4 μM 22 23% @ 100 μM 23 4.70 μM

The compounds of this invention are useful in treating or inhibitingdiseases which are characterized by excessive smooth muscle cellproliferation (smooth muscle cell hyperproliferation). The compounds areparticularly useful in treating hyperproliferative vascular diseaseswhich are characterized by smooth muscle cell hyperproliferation, suchas restenosis, which most frequently arises from vascular reconstructivesurgery and transplantation, for example, balloon angioplasty, vasculargraft surgery, coronary artery bypass surgery, and hearttransplantation. Other disease states in which there is unwanted“cellular” vascular proliferation include hypertension, asthma, andcongestive heart failure. The compounds of this invention are alsouseful as inhibitors of angiogenesis. Angiogenesis (neovascularization),the process by which new capillaries are formed, is of principalimportance for a number of pathological events including chronicinflammation and malignant processes. The compounds of this inventionare therefore useful as antineoplastic agents.

The compounds of this invention can be formulated neat or with apharmaceutical carrier for administration, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmacological practice. Thepharmaceutical carrier may be solid or liquid.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,lethicins, and oils (e.g. fractionated coconut oil and arachis oil). Forparenteral administration, the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usefulin sterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compounds of this invention can also beadministered orally either in liquid or solid composition form.

The compounds of this invention may be administered rectally orvaginally in the form of a conventional suppository. For administrationby intranasal or intrabronchial inhalation or insufflation, thecompounds of this invention may be formulated into an aqueous orpartially aqueous solution, which can then be utilized in the form of anaerosol. The compounds of this invention may also be administeredtransdermally through the use of a transdermal patch containing theactive compound and a carrier that is inert to the active compound, isnon toxic to the skin, and allows delivery of the agent for systemicabsorption into the blood stream via the skin. The carrier may take anynumber of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments may be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient may also besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semipermeable membranecovering a reservoir containing the active ingredient with or without acarrier, or a matrix containing the active ingredient. Other occlusivedevices are known in the literature.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Based on the results obtained inthe standard pharmacological test procedures, projected daily dosages ofactive compound would be 0.1 to 10 mg/kg administered parenterally(intravenous preferred), with projected daily oral dosage beingapproximately ten-fold higher. Anticipated intravenous administrationwould last for approximately 5-30 days following acute vascular injury(i.e., balloon angioplasty or transplantation) and for a longer durationfor the treatment of chronic disorders. Treatment will generally beinitiated with small dosages less than the optimum dose of the compound.Thereafter the dosage is increased until the optimum effect under thecircumstances is reached; precise dosages for oral, parenteral, nasal,or intrabronchial administration will be determined by the administeringphysician based on experience with the individual subject treated.Preferably, the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packaged powders, vials, ampoules, pre filled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form.

The following provides the preparation of representative compounds ofthis invention.

EXAMPLE 1 4-Chloro-3-nitro-benzyl-β-D-maltoside heptaacetate

To a stirred solution of 4-chloro-3-nitrobenzyl alcohol (6.70 g, 35.7mmol) and HgBr₂ (14.2 g, 39.3 mmol) in freshly distilled CH₃CN (239 mL)was added in one portion Hg(CN)₂ (9.02 g, 35.7 mmol). After 0.5 h,acetobromomaltose (25.0 g, 35.7 mmol) was added, and the mixture stirredfor 18 h at rt. The reaction was then quenched with a mixture ofH₂O:brine (1:1, 100 mL) and extracted with 10% CH₂Cl₂:EtOAc. Thecombined organic extracts were dried (MgSO₄) and concentrated.Purification by flash chromatography (10:90 to 80:20 EtOAc:petroleumether gradient) gave 51.9 g (90%) of the title compound as a glassy oilwhich was recrystallized from EtO:petroleum ether to afford a glassywhite solid, mp 107-111° C.; ¹H NMR (CDCl₃) δ 2.00 (s, 3H), 2.02 (s,3H), 2.03, (s, 3H), 2.04 (s, 6H), 2.11 (s, 3H), 2.15 (s, 3H), 3.70 (ddd,J=2.9, 4.2, 9.7 Hz, 1H), 3.94-3.98 (m, 1H), 4.01-4.07 (m, 2H), 4.20-4.28(m, 2H), 4.54 (dd, J=2.9, 12.3 Hz, 1H), 4.63-4.68 (m, 2H), 4.84-4.94 (m,3H), 5.06 (t, J=10.1 Hz, 1H), 5.26 (t, J=9.2 Hz, 1H), 5.36 (dd, J=9.7,10.3 Hz, 1H), 5.42 (d, J=4.2 Hz, 1H), 7.43 (dd, J=2.2, 8.3 Hz, 1H), 7.53(d, J=8.3 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H); IR (KBr) 3450, 2950, 1755,1550, 1375, 1230 and 1050 cm⁻¹; mass spectrum [(+) ESI], m/z 823/825(M+NH₄ ⁺), 828/830 (M+Na)⁺; Anal. Calcd. for C₃₃H₄₀ClNO₂₀: C, 49.17; H,5.00; N, 1.74, Found: C, 49.16; H, 4.88; N. 1.71.

EXAMPLE 2N-{5-[(Hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}1-L-aspartamide-γ-tert-butylester

Step 1

2-Chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine

A solution containing 4-chloro-3-nitro-benzyl-β-D-maltoside heptaacetate(Example 1, 19.3 g, 23.9 mmol) and tin (II) chloride dihydrate (37.7g,167 mmol) in EtOAc (479 mL) was refluxed for 2 h. The reaction wascooled to rt, carefully quenched with sat. aq. NaHCO₃ (until basic),diluted with EtOAc (250 mL), stirred for 0.5 h and filtered. Thebiphasic filtrate was separated and the aqueous phase extracted withEtOAc. The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification by flash chromatography (0 to 12%acetone/CHCl₃ gradient) gave 17.8 g (96%)2-Chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine as aglassy solid, mp 78-79° C.; ¹H NMR (CDCl₃) δ 2.00 (s, 9H), 2.026 (s,3H), 2.032 (s, 3H), 2.11 (s, 3H), 2.16 (s 3H), 3.00-5.00 (bs, 2H),3.64-3.68 (m, 1H), 3.97 (ddd, J=2.4, 4.2, 10.1 Hz, 1H), 4.02-4.07 (m,2H), 4.24 (dd, J=2.2, 3.7, 1H), 4.27 (dd, J=2.6, 4.0 Hz, 1H), 4.50-4.57(m, 3H), 4.74 (d, J=12.1 Hz, 1H), 4.83-4.90 (m, 2H), 5.05 (t, J=10.1 Hz,1H), 5.22 (t, J=9.2 Hz, 1H), 5.35 (dd, J=9.7, 10.5 Hz, 1H), 5.42 (d,J=4.0 Hz, 1H), 6.62 (dd, J=2.0, 8.1 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H),7.21 (d, J=8.1, 1H); IR (KBr) 3450, 3350, 2950, 1755, 1650, 1425, 1375,1230 and 1050 cm⁻¹; mass spectrum [(+) ESI], m/z 776/778 (M+H)⁺, 798/800(M+Na)⁺; Anal. Calcd. for C₃₃H₄₂ClNO₁₈: C, 51.07; H, 5.45; N, 1.80,Found: C, 50.94; H, 5.52; N, 1.60.

Step 2

N-{5-[(Hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}-(9H-fluoren-9-ylmethyoxycarbonylamino)-L-aspartamide-4-tert-butylester

To a stirred solution ofN-(9H-fluoren-9-ylmethyoxycarbonylamino)-L-aspartic acid-4-tert-butylester (0.117 g, 0.284 mmol) and DMF (cat. amt.) in CH₂Cl₂ (3 mL) at rtwas added oxalyl chloride (24.8 μL, 0.284 mmol) dropwise. After 5 min.at this temperature, it was heated to 40° C. for an additional 10 min.This completed the preparation of the acid chloride starting material.At this point, to a second stirred solution of NaH (0.0103 g, 0.258mmol) and CH₂Cl₂ (4 mL) at rt was added2-chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine (0.200mg, 0.258 mmol). After 10 min., the acid chloride solution was added tothis solution dropwise. The reaction was stirred at rt for 1 h and thendiluted with EtOAc (100 mL). This layer was washed with 1N HCl (10 mL),sat. NaHCO₃ (10 mL), and brine (10 mL) and then dried (MgSO₄). Afterconcentration, the oilly residue was purified by flash chromatography(10:90 to 70:30 EtOAc:petroleum ether gradient) to afford the product(0.157 g, 52%) as a white foam, mp 103-105° C.; ¹H NMR (CDCl₃) δ 1.46(s, 9H), 1.99 (s, 3H), 2.00 (s, 3H), 2.01 (s, 3H), 2.02 (s, 3H), 2.03(s, 3H), 2.10 (s, 3H), 2.16 (s, 3H), 2.70 (dd, J=5.9, 17.4 Hz, 1H),2.96-3.06 (m, 1H), 3.67 (ddd, J=2.6, 4.2, 9.7 Hz, 1H), 3.96 (ddd, J=2.4,3.7, 10.3 Hz, 1H), 4.00-4.06 (m, 2H), 4.22-4.28 (m, 3H), 4.42-4.48 (m,1H), 4.48-4.56 (m, 2H), 4.58 (dd, J=2.2, 10.1 Hz, 2H), 4.68-4.76 (m,1H), 4.81-4.91 (m, 3H), 5.05 (t, J=10.1 Hz, 1H), 5.22 (t, J=9.2 Hz, 1H),5.35 (dd, J=9.7, 10.5 Hz, 1H), 5.41 (d, J=4.0 Hz, 1H), 6.07-6.15 (m,1H), 7.00 (dd, J=2.0, 8.1 Hz, 1H), 7.28-7.36 (m, 3H), 7.40 (t, J=7.2 Hz,2H), 7.57-7.62 (m, 2H), 7.77 (d, J=7.5 Hz, 2H), 8.31 (d, J=1.8 Hz, 1H),8.86 (s, 1H); IR (KBr) 3380, 2960, 1755, 1600, 1540, 1440, 1420, 1375,1230, 1160, and 1050 cm⁻¹; mass spectrum [(+) FAB], m/z 1169 (M+H)⁺,1191 (M+Na)⁺; Anal. Calcd. for C₅₆H₆₅ClN₂O₃.2.0 H₂O: C, 55.79; H, 5.77;N, 2.32, Found: C, 55.89; H, 5.45; N, 2.25.

Step 3

N-{5-[(Hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}-L-aspartamide-γ-tert-butylester

To a stirred solution of 20% piperidine (2.00 mL, 20.2 mmol) in DMF (10mL) at rt was addedN-{5-[(hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}-(9H-fluoren-9-ylmethyoxycarbonylamino)-L-aspartamide-4-tert-butylester (0.300 g, 0.256 mmol). After 1 h at this temperature, the solutionwas concentrated on the high vacuum. At this point, the residue wasdiluted with cold H₂O (20 mL) and then extracted with Et₂O (50 mL). Thislayer was dried (Na₂SO₄) and after concentration, the resulting oil waspurified by flash chromatography (20:80 to 90:10 EtOAc:petroleum ethergradient) to afford the product (0.186 g, 77%) as a white solid, mp85-87° C.; ¹H NMR (CDCl₃) δ 1.45 (s, 9H), 1.89 (s, 2H), 1.99 (s, 6H),2.01 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 2.10 (s, 3H), 2.16 (s, 3H),2.68 (dd, J=8.1,.16.7 Hz, 1H), 2.91 (dd, J=3.7, 16.7 Hz, 1H), 3.64-3.69(m, 1H), 3.80 (dd, J=3.7, 8.3 Hz, 1H), 3.93-3.98 (m, 1H), 3.99-4.05 (m,211), 4.21-4.27 (m, 2H), 4.50 (dd, J=2.6, 12.1 Hz, 1H), 4.56 (d, J=3.7Hz, 1H), 4.59 (d, J=8.1 Hz, 1H), 4.81-4.91 (m, 3H), 5.05 (t, J=10.1 Hz,1H), 5.22 (t, J=9.4 Hz, 1H), 5.34 (dd, J=9.4, 10.3 Hz, 1H), 5.40 (d,J=4.0 Hz, 1H), 6.98 (dd, J=2.0, 8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H),8.42 (d, J=2.0 Hz, 1H), 10.28 (s, 1H); IR (KBr) 3380, 2960, 1755, 1600,1540, 1440, 1420, 1375, 1235, 1140, and 1040 cm⁻¹; mass spectrum [(+)FAB], m/z 947/949 (M+H)⁺, 969/971 (M+Na)⁺; Anal. Calcd. forC₄₁H₅₅ClN₂O₂₁: C, 51.98; H, 5.85; N, 2.96, Found: C, 51.62; H, 5.89; N,2.95.

EXAMPLE 3N-{2-Chloro-5-[(2,2′,3,3′,4′,6,6′)-hepta-O-acetyl-β-D-maltosyl-oxymethyl]-phenyl}-(9H-fluoren-9-ylmethoxycarbonyl)-L-alaninamide

The title compound was prepared as a white foam (2.50 g, 36%) from2-chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine usingN-(9H-fluoren-9-ylmethyoxycarbonylamino)-L-alanine and a proceduresimilar to step 2 of Example 2, mp >96° C. (decomp.); ¹H NMR (DMSO-d₆) δ1.33 (dd, J=7.2 Hz, 3H), 1.918 (s, 3H), 1.919 (s, 3H), 1.94 (s, 3H),1.966 (s, 3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 3.91-4.02 (m,4H), 4.12-4.24 (m, 3H), 4.24-4.34 (m, 3H), 4.34-4.40 (m, 1H), 4.53 (d,J=12.7 Hz, 1H), 4.68-4.75 (m, 2H), 4.84 (d, J=4.0 Hz, 1H), 4.86 (d,J=2.6 Hz, 1H), 4.97 (t, J=9.7 Hz, 1H), 5.21 (t, J=9.7 Hz, 1H), 5.27 (d,J=3.7 Hz, 1H), 5.27-5.32 (m, 1H), 7.08 (dd, J=1.8, 8.1 Hz, 1H), 7.32 (t,J=7.2 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.47 (d, J=8.1 Hz, 1H), 7.69-7.78(m, 4H), 7.88 (d, J=7.5 Hz, 2H), 9.42 (s, 1H); IR (KBr) 3360, 3010,2950, 1755, 1590, 1535, 1440, 1420, 1370, 1230, 1050, and 755 cm⁻¹; massspectrum [(+) ESI], m/z 1069.2 (M+H)⁺, 1086.2/1088.2 (M+NH₄)⁺; Anal.Calcd. for C₅₁H₅₇ClN₂O₂₁.3.5 H₂O: C, 54.09; H, 5.70; N, 2.47, Found: C,53.67; H, 5.11; N, 2.34.

EXAMPLE 44-Benzoyl-N-{2-chloro-5-[(2,2′,3,3′,4′,6,6′-hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-phenyl}-benzamide

The title compound was prepared as a white foam (0.240 g, 94%) from2-chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine usingp-benzoylbenzoic acid and a procedure similar to step 2 of Example .2,mp >84° C. (decomp.); ¹H NMR (DMSO-d₆) δ 1.93 (s, 3H), 1.94 (s, 6H),1.97 (s, 6H), 2.01 (s, 3H), 2.08 (s, 3H), 3.93-4.03 (m, 4H), 4.15 (dd,J=4.6, 12.3 Hz, 1H), 4.21 (dd, J=4.6, 12.1 Hz, 1H), 4.39 (dd, J=2.2,11.9 Hz, 1H), 4.70 (ABq, J=12.7 Hz, Δδ=0.14, 2H), 4.74 (dd, J=8.1, 9.7Hz, 1H), 4.86 (dd, J=4.0, 10.5 Hz, 1H), 4.90 (d, J=8.1 Hz, 1H), 4.98 (t,J=9.7 Hz, 1H), 5.21 (dd, J=9.7, 10.5 Hz, 1H), 5.28 (d, J=4.0 Hz, 1H),5.31 (dd, J=8.6, 9.4 Hz, 1H), 7.22 (dd, J=2.0, 8.3 Hz, 1H), 7.52 (d,J=2.0 Hz, 1H), 7.55-7.62 (m, 3H), 7.69-7.74 (m, 1H), 7.76-7.80 (m, 2H),7.85-7.88 (m, 2H), 8.11-8.14 (m, 2H), 10.30 (s, 1H); IR (KBr) 3400,3010, 2950, 1755, 1675, 1650, 1590, 1530, 1440, 1420, 1370, 1230, 1130,and 1040 cm⁻¹; mass spectrum [(+) FAB], m/z 984/986 (M+H)⁺, 1006/1008(M+Na)⁺; Anal. Calcd. for C₄₇H₅₀ClNO₂₀: C, 57.35; H, 5.12; N, 1.42,Found: C, 57.11; H, 5.03; N, 1.32.

EXAMPLE 5 (4-Chloro-3-nitro-benzyl)-hepta-O-acetyl-1-thio-β-D-maltoside

To a stirred solution of hepta-O-acetyl-1-thio-β-maltose (2.0 g, 3.065mmol) [P. L. Durette; T. Y. Shen. Carb. Res. 1978, 67, 484-490.] inacetone (20 ml) were added 4-chloro-3-nitrobenzyl bromide (0.844 mg,3.37 mmol) and a solution of potassium carbonate (0.423 mg, 3.065 mmol)in water (10 ml). The mixture was boiled under reflux for 30 min, cooledand concentrated. The residue was extracted with dichloromethane, andthe combined extracts were washed with water, and brine, dried (MgSO₄)and concentrated. Purification by flash chromatography (40%-60%EtOAc/petroleum ether gradient) afforded 1.588 g (63%) of the titlecompound as a white solid, mp 73-75° C.; ¹H NMR (CDCl₃) δ 1.99 (s, 3H),2.00 (s, 3H), 2.02 (s, 3H), 2.03 (s, 6H), 2.11 (s, 3H), 2.15 (s, 3H),3.61-3.64 (m, 1H), 3.80 (d, J=13.6 Hz, 1H), 3.94-4.00 (m, 3H), 4.08 (dd,J=12.3, 2.4 Hz, 1H), 4.18-4.27 (m, 2H), 4.36 (d, J=9.9 Hz, 1H), 4.50(dd, J=12.1, 2.6 Hz, 1H), 4.85 (dd, J=10.5, 4.0 Hz, 1H), 4.90 (apparantt, J=9.9 Hz, 1H), 5.05 (apparant t, J=9.9 Hz, 1H), 5.23 (apparant t,J=9.2 Hz, 1H), 5.34 (apparant t, J=9.7 Hz, 1H), 5.40 (d, J=4.0 Hz, 1H),7.47 (dd, J=8.4, 2.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.87 (d, J=2.0,Hz, 1H); IR (KBr) 3500, 2950, 1750, 1250 and 1050 cm⁻¹; mass spectrum[(+) FAB], m/z 822 (M+H)⁺, 844 (M+Na)⁺; Anal. Calcd. for C₃₃H₄₀ClNO₁₉S:C, 48.21; H, 4.90; N, 1.70, Found: C, 47.75; H, 4.86; N, 1.65.

EXAMPLE 6 (3-Amino-4-chloro-benzyl) hepta-O-acetyl-1-thio-β-D-maltoside

The title compound was prepared as a white solid from(4-chloro-3-nitro-benzyl)-hepta-O-acetyl-1-thio-β-D-maltoside using aprocedure similar to step 1 of Example 2, mp 78° C.; ¹H NMR (CDCl₃) δ1.99 (s, 9H), 2.02 (s, 3H), 2.03 (s, 3H), 2.11 (s, 3H), 2.18 (s, 3H),3.57-3.60 (m, 1H), 3.73 (ABq, J=13.0 Hz, Δδ=0.16, 2H), 3.95-4.08 (m,3H), 4.17 (bs, 2H), 4.23 (d, J=4.2, Hz, 2H), 4.27 (dd, J=7.7, 4.4 Hz,1H), 4.31 (d, J=4.4, Hz, 1H), 4.34 (d, J=10.1, Hz, 1H), ), 4.44 (dd,J=12.1, 3.3 Hz, 1H), ), 4.84 (dd, J=10.5, 4.0 Hz, 1H), 4.88 (apparant t,J=9.9 Hz, 1H), 5.03 (apparant t, J=9.9 Hz, 1H), 5.35 (apparant t, J=9.0Hz, 1H), 5.35 (apparant t, J=9.4 Hz, 1H), 5.40 (d, J=4.0, Hz, 2H), 6.60(dd, J=8.1, 2.0 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 7.18 (d, J=8.13 Hz,1H); IR (KBr) 3500, 2950, 1750, 1245 and 1050 cm⁻¹; mass spectrum [(−)FAB], m/z 790 (M−H)⁻; Anal. Calcd. for C₃₃H₄₂ClNO₁₇: C, 50.03; H, 5.34;N, 1.77, Found: C, 49.55; H, 5.21; N, 1.71.

EXAMPLE 7N-{2-Chloro-5-[hepta-O-acetyl-β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamide

The title compound was prepared as a white solid from(3-amino-4-chloro-benzyl) hepta-O-acetyl-1-thio-β-D-maltoside using aprocedure similar to step 1 of Example 9, mp 80-81° C.; ¹H NMR (CDCl₃) δ1.99 (s, 9H), 2.03 (s, 6H), 2.11 (s, 3H), 2.16 (s, 3H), 2.25 (s, 3H),3.61-3.65 (m, 1H), 3.82 (ABq, J=13.2 Hz, Δδ=0.14, 2H), 3.94-4.11 (m,3H), 4.34 (d J=10.1 Hz, 1H), 4.53 (dd, J=12.3, 2.6 Hz, 1H), 4.83-4.91(m, 2H), 5.05 (apparant t, J=9.7 Hz, 1H), 5.20 (apparant t, J=9.0 Hz,1H), 5.34 (apparant t, J=10.3 Hz, 1H), 5.39 (d, J=4.2 Hz, 1H), 7.00 (dd,J=8.1, 2.2 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 8.31 (s, 1H);IR (KBr) 3400, 2955, 1750, 1245 and 1050 cm⁻¹; mass spectrum [(+) FAB],m/z 834 (M+H)⁺, 856 (M+Na)⁺; Anal. Calcd. for C₃₅H₄₄ClNO₁₈ S: C, 50.39;H, 5.32; N, 1.68, Found: C, 49.99; H, 5.07; N, 1.59.

EXAMPLE 85-[(Hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-2-cyano-1-nitrobenzene

Step 1

α-Bromo-2-nitro-p-tolunitrile

A stirred mixture containing 4-methyl-2-nitrobenzonitrile (2.04 g, 12.6mmol), N-bromosuccinimide (2.24 g, 12.6 mmol) and azobisisobutyronitrile(0.103 g, 0.630 mmol) in CCl₄ (50 mL) was irradiated with a 300 wattflood light for 2 h. The reaction was diluted with CH₂Cl₂ (50 ml),filtered and concentrated. Purification by flash chromatography (35 and40% ether/pet. ether gradient) gave 1.44 g (47%) of the title compoundas a yellow oil. ¹H NMR (DMSO-d₆) δ 4.90 (s, 2H), 8.05 (dd, J=8.0, 1.5Hz, 1H), 8.18 (d, J=8.0, 1H), 8.52 (s, 1H).

Step 2

α-Hydroxy-2-nitro-p-tolunitrile

A stirred solution containing α-bromo-2-nitro-p-tolunitrile (1.228 g,5.095 mmol) and sodium formate (0.8664 g, 12.74 mmol) in ethanol:water(4:1, 25 mL) was refluxed for 2 h. The reaction was cooled to roomtemperature, diluted with 20% CH₂Cl₂/EtOAc, washed with H2O (3×), dried(MgSO₄) and concentrated. Purification by flash chromatography (1, 2 and3% MeOH/CHCl₃ gradient) gave 0.695 g (77%) of the title compound as awhite solid. ¹H NMR (DMSO-d₆) δ 4.71 (d, 2H), 5.75 (t, 1H), 7.89 (dd,J=7.9 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 8.32 (s, 1H).

Step 3

5-[(Hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-2-cyano-1-nitrobenzene

At ambient temperature, to a stirred solution of acetobromomaltose (2.39g, 3.41 mmol), α-hydroxy-2-nitro-p-tolunitrile (0.789 g, 4.43 mmol) andHgBr₂ (1.60 g, 4.43 mmol) in freshly distilled CH₃CN (34 mL) was addedin one portion Hg(CN)₂ (1.12 g, 4.43 g, mmol). After 16 h, brine (50 mL)was added and the mixture was extracted with 10% CH₂Cl₂/EtOAc. Thecombined organic extracts were washed with brine (3×), dried (MgSO4) andconcentrated. Purification by flash chromatography (1, 2 and 3%MeOH/CHCl₃ gradient) gave 1.941 g (71%) of the title compound as a foam.An analytical sample was obtained by recrystallization from EtOAc/Hexanefollowed by recrystallization from EtOH to give a white solid, mp155-157° C.; ¹H NMR (DMSO-d₆) δ 1.93 (s, 3H), 1.94 (s, 3H), 1.97 (s,3H), 1.99 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H), 3.93-4.01 (m, 4H), 4.36(d, J=11.0 Hz, 1H), 4.77 (dd, J=9.6, 8.0 Hz, 1H), 4.83-4.88 (m, 2H),4.93-5.00 (m, 3H), 5.21 (dd, J=10.3, 9.7 Hz, 1H), 5.27 (d, J=3.7 Hz,1H), 5.30-5.34 (m, 1H), 7.84 (dd, J=7.9, 1.5 Hz, 1H), 8.18 .(d, J=7.9Hz, 1H), 8.27 (s, 1H); IR (KBr) 3450, 2950, 2225, 1750, 1225 and 1050cm⁻¹; mass spectrum [(+) FAB], m/z 797 (M+H)⁺; Anal. Calcd. forC₃₄H₄₀N₂O₂₀: C, 51.26; H, 5.06; N, 3.52, Found: C, 51.06; H, 5.02; N,3.31.

EXAMPLE 9 N-[2-Chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-adetamide

Step 1

N-[2-Chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenyl]-

To a stirred solution of2-chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine (20.6 g,26.5 mmol) and triethylarnine (8.13 mL, 58.3 mmol) in THF (265 mL) at 0°C. was added dropwise acetyl chloride (2.26 mL, 31.8 mmol). After 0.5 hat this temperature, it was warmed to rt and stirred an additional 6 h.At this point, the reaction was concentrated and taken up in EtOAc (700mL). This organic solution was washed with 1 N HCl (70 mL), sat. aq.NaHCO₃ (70 mL), and brine (70 mL) and then dried (MgSO₄). Afterconcentration, the residue was purified by flash chromatography (20:80to 100:0 EtOAc:petroleum ether gradient) to afford the product (16.2 g,75%) as a glassy solid, mp 84-86° C.; ¹H NMR (CDCl₃) δ 2.00 (s, 6H),2.020 (s, 3H), 2.027 (s, 3H), 2.03 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H),2.24 (s, 3H), 3.66-3.69 (m, 1H), 3.94-3.98 (m, 1H), 4.00-4.06 (m, 2H),4.22-4.28 (m, 2H), 4.50-4.61 (m, 3H), 4.80-4.91 (m, 3H), 5.05 (t, J=10.1Hz, 1H), 5.22 (t, J=9.2 Hz, 1H), 5.35 (dd, J=9.4, 10.5 Hz, 1H), 5.41 (d,J=4.0 Hz, 1H), 6.99 (dd, J=2.0, 8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H),7.62 (s, 1H), 8.32 (s, 1H); IR (KBr) 3400, 2950, 1750, 1690, 1600, 1540,1425, 1375, 1230 and 1050 cm⁻¹; mass spectrum [(+) ESI], m/z 818/820(M+H)⁺, 840 (M+Na)⁺; Anal. Calcd. for C₃₅H₄₄ClNO₁₉: C, 51.38; H, 5.42;N, 1.71, Found: C, 51.03; H, 5.36; N, 1.59.

Step 2

N-[2-Chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetamide

A solution containingN-[2-chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenyl]-acetamide(0.945 g, 1.12 mmol) and 25 weight % NaOMe in MeOH (19.2 μL, 0.336 mmol)in MeOH (27.6 ml) was refluxed for 2.5 h. The reaction was cooled toroom temperature and concentrated, and the resulting residue wastriturated with EtO to afford the product (0.583 g, 99%) as a foam; ¹HNMR (DMSO-d₆) δ 2.07 (s, 3H), 3.03-3.16 (m 2H), 3.19-3.49 (m, 7H),3.55-3.62 (m, 2H), 3.67-3.73 (m, 1H), 4.28 (d, J=7.7 Hz, 1H), 4.33-5.76(bs, 7H), 4.67 (ABq, J=12.5 Hz, Δδ=0.22, 2H), 5.01 (d, J=3.7 Hz, 1H),7.21 (dd, J=1.8, 8.1 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.64 (d, J=1.5 Hz,1H), 9.33-9.69 (bs, 1H); IR (KBr) 3400, 2900, 1680, 1600, 1540, 1430,1375, 1310, 1150 and 1035 cm⁻¹; mass spectrum [(+) ESI], m/z 524/526(M+H)⁺, 546 (M+Na)⁺; Anal. Calcd. for C₂₁H₃₀ClNO₁₂.1.0 MeOH: C, 47.53;H, 6.16; N, 2.52, Found: C, 47.94; H, 6.34; N, 2.42.

EXAMPLE 10N-{5-[6,6′-Di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-2-methyl-phenyl}-acetamide

To a stirred solution ofN-[5-(β-D-maltosyl-oxymethyl)-2-methyl-phenyl]-acetanide (prepared from4-methyl-3-nitrobenzyl alcohol and acetobromomaltose using proceduressimilar to Example 1, Example 2—step 1, and Example 9) (1.5 g, 2.98mmol) in CH₂Cl₂:DMF (1:1, 12 mL) at rt was added DMAP (0.109 g, 0.892mmol) followed by triethylamine (1.66 mL, 11.9 mmol), and then finallyTBDMSCl (1.35 g, 8.96 mmol). After 18, the solvent was removed on highvac and the residue diluted with EtOAc (200 mL). This organic layer waswashed with 1 N HCl (20 mL), sat. aq. NaHCO₃ (20 mL), and brine (20 nlL)and then dried (MgSO₄). After concentration, the residue was purified byflash chromatography (0:100 to 25:75 MeOH:CHCl₃ gradient) to afford theproduct (16.2 g, 75%) as a white foam, mp 111-114° C.; ¹H NMR (CDCl₃) δ0.067 (s, 6H), 0.080 (s, 3H), 0.084 (s, 3H), 0.89 (s, 9H), 0.90 (s, 9H),2.07 (s, 3H), 2.16 (s, 3H), 3.25-3.28 (m, 1H), 3.34-3.38 (m, 1H),3.45-3.52 (m, 3H), 3.65-3.78 (m, 4H), 3.84-3.94 (m, 4H), 4.28 (d, J=7.7Hz, 1H), 4.64 (ABq, J=12.1 Hz, Δδ=0.27, 2H), 4.65-4.69 (bs, 1H),4.74-4.78 (m, 1H), 4.97 (d, J=3.3 Hz, 1H), 5.25-5.30 (m, 1H), 5.63-5.68(bs, 1H), 6.99 (d, J=7.9 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.54 (s, 1H),7.59-7.63 (bs, 1H); IR (KBr) 3400, 2930, 2870, 1670, 1600, 1550, 1450,1375, 1255, 1125, 1050, 840, and 790 cm⁻¹; mass spectrum [(+) FAB], m/z754 (M+Na)⁺; Anal. Calcd. for C₃₄H₆₁NO₁₂Si₂.0.5 H₂O: C, 55.11; H, 8.43;N, 1.89, Found: C, 54.91; H, 8.36; N, 1.85.

EXAMPLE 11N-{2-Chloro-5-[6,6′-di-O-(tert-butyl-dimethyl-silvl)-β-D-maltosyloxy-methyl]-phenyl}-acetamide

The title compound was prepared as a white foam (0.845 g, 59%) fromN-[2-chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetamide using aprocedure similar to Example 10, mp 93-98° C.; ¹H NMR (CDCl₃) δ 0.07 (s,12H), 0.88 (s, 9H), 0.89 (s, 9H), 2.18 (s, 3H), 3.25-3.31 (m, 1H),3.41-3.46 (m, 1H), 3.49-3.58 .(m, 3H), 3.69-3.79 (m, 4H), 3.85 (d, J=4.0Hz, 1H), 3.87-3.92 (m, 2H), 3.92 (d, J=2.6 Hz, 1H), 4.32 (d, J=7.7 Hz,1H), 4.53-4.58 (m, 1H), 4.68 (ABq, J=12.5 Hz, Δδ=0.25, 2H), 4.71-4.75(m, 1H), 5.00 (d, J=3.5 Hz, 1H), 5.25 (dd, J=2.0, 6.4 Hz, 1H), 5.69 (s,1H), 6.98-7.04 (m, 1H), 7.25-7.29 (m, 1H), 7.66 (s, 1H), 8.25 (s, 1H);IR (KBr) 3400, 2930, 2880, 1675, 1600, 1550, 1460, 1420, 1365, 1250,1050, 850, and 800 cm⁻¹; mass spectrum [(+) FAB], m/z 774/776 (M+Na)⁺;Anal. Calcd. for C₃₃H₅₈ClNO₁₂Si₂.0.5 H₂O: C, 52.05; H, 7.81; N, 1.84,Found: C, 52.16; H, 7.82; N, 1.80.

EXAMPLE 12N-{2-Chloro-5-[([6,6′-di-O-benzoyl-β-D-maltosyl]oxy)methyl]phenyl}-acetamide

To a stirred solution ofN-[2-chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetamide (1.00 g, 1.91mmol) in THF (20.0 mL) at −40° C. was added collidine (20.0 mL, 151mmol) followed by dropwise addition of benzoyl chloride (0.532 mL, 4.58mmol). After 2 h at this temperature, it was warmed to rt and stirred anadditional 18 h. At this point, the solvent was distilled off using thehigh vac, and the residue was purified by flash chromatography (2% to20% MeOH:CHCl₃ gradient) to afford the product (0.500 g, 36%) as aglassy white solid, mp 99-100° C.; ¹H NMR (CDCl₃) δ 2.12 (s, 3H),3.41-3.51 (m, 3H), 3.59-3.68 (m, 2H), 3.77 (t, J=9.2 Hz, 1H), 3.85 (t,J=9.2 Hz, 1H), 4.06-4.12 (m, 1H), 4.30-4.34 (m, 2H), 4.40-5.35 (bs, 3H),4.51 (dd, J=5.3, 12.1 Hz, 1H), 4.57 (ABq, J=12.5 Hz, Δδ=0.22, 2H), 4.59(d, J=10.5 Hz, 1H), 4.80 (d, J=11.0 Hz, 1H), 5.07 (d, J=3.1 Hz, 1H),5.45-5.66 (bs, 1H), 5.75-5.95 (bs, 1H), 6.86 (dd, J=1.3, 8.3 Hz, 1H),7.12 (d, J=8.3 Hz, 1H), 7.23 (t, J=7.7 Hz, 2H), 7.33-7.52 (m, 4H), 7.70(s, 1H), 7.91-7.96 (m, 4H), 8.14 (s, 1H); IR (KBr) 3400, 2900, 1720,1620, 1600, 1550, 1450, 1425, 1375, 1320, 1225, 1100, and 1060 cm⁻¹;mass spectrum [(+) FAB], m/z 732 (M+H)⁺, 754 (M+Na)⁺; Anal. Calcd. forC₃₅H₃₈ClNO₁₄.0.5 H₂O: C, 56.72; H, 5.30; N, 1.89, Found: C, 56.62; H,5.04; N, 1.90.

EXAMPLE 13N-{2-Chloro-5-[([6,6′-di-O-benzoyl-2,2′,3,3′,4′-penta-acetyl-β-D-maltosyl]oxy)methyl]phenyl}-acetamide

To a stirred solution ofN-{5-[([6,6′-di-O-benzoyl-β-D-maltosyl]oxy)methyl]-2-chlorophenyl}-acetamide(0.122 g, 0.167 mmol) and triethylamine (0.256 mL, 1.84 mmol) in CH₂Cl₂(5.0 mL) at rt was added dropwise acetic anhydride (0.0865 mL, 0.916mmol) followed by a catalytic amount of DMAP (0.0102 g, 0.0835 mmol).After 18 h, the mixture was diluted with EtOAc (50 mL). This layer waswashed with 1 N HCl (5 mL), sat. aq. NaHCO₃ (5 mL), and brine (5 mL) andthen dried (MgSO₄). After concentration, the residue was purified byflash chromatography (2% to 20% acetone:CHCl₃ gradient) to afford theproduct (1.68 g, 94%) as a fine white powder (0.120 g, 76%), mp 97-100°C.; ¹H NMR (CDCl₃) δ 1.96 (s, 3H), 1.99 (s, 3H), 2.01 (s, 3H), 2.03 (s,3H), 2.04 (s, 3H), 2.22 (s, 3H), 3.80-3.84 (m, 1H), 4.06-4.10 (m, 1H),4.18-4.22 (m, 3H), 4.53 (dd, J=4.0, 12.3 Hz, 1H), 4.58 (d, J=9.7 Hz,1H), 4.61 (d, J=5.1 Hz, 1H), 4.76-4.79 (m, 1H), 4.79-4.82 (m, 1H), 4.86(dd, J=4.0, 10.5 Hz, 1H), 4.92 (dd, J=7.7, 9.2 Hz, 1H), 5.15 (t, J=9.9Hz, 1H), 5.27 (t, J=9.0 Hz, 1H), 5.41 (dd, J=9.7, 10.3 Hz, 1H), 5.47 (d,J=4.2 Hz, 1H), 6.95 (dd, J=1.8, 8.1 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H),7.41-7.50 (m, 4H), 7.52-7.62 (m, 3H), 7.98-8.01 (m, 2H), 8.07-8.09 (m,2H), 8.30 (s, 1H); IR (KBr) 3400, 2950, 1760, 1725, 1620, 1600, 1550,1450, 1425, 1375, 1275, 1245, 1120, 1050, and 710 cm⁻¹; mass spectrum[(+) FAB], m/z 942 (M+H)⁺, 964 (M+Na)⁺; Anal. Calcd. forC₄₅H₄₈ClNO₁₉.2.0 H₂O: C, 55.25; H, 5.36; N,.1.43, Found: C, 55.18; H,4.87; N, 1.36.

EXAMPLE 14(4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside-6-(3-pyridinecarboxylate)

To a stirred solution ofN-[2-chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetamide (0.500 g, 0.977mmol) in THF (9.8 mL) at 40° C. was added collidine (9.8 mL, 74.3 mmol)dropwise followed by nicotinoyl chloride hydrochloride (0.417 g, 2.34mmol). After 2 h at this temperature, it was warmed to rt and stirred anadditional 42 h. At this point, the reaction was concentrated on highvacuum and then diluted with EtOAc (250 mL). The solid was filtered offand washed with additional EtOAc (50 mL). The filtrate was concentrated,and the resulting oilly residue purified by flash chromatography (40:2:1to 10:2:1 EtOAc:EtOH:H₂O gradient) to afford the product (0.159 g, 23%)as a white solid, mp 145-147° C.; ¹H NMR (DMSO-d₆) δ 3.15-3.25 (m, 2H),3.32-3.35 (m, 1H), 3.43 (dd, J=5.3, 9.2 Hz, 1H), 3.45-3.52 (m, 1H), 3.54(t, J=8.8 Hz, 1H), 3.70-3.76 (m, 1H), 3.91 (ddd, J=1.3, 5.5, 9.7 Hz,1H), 4.29-4.38 (m,.2H), 4.41 (d, J=7.7 Hz, 1H), 4.53-4.58 (m, 1H),4.67-4.72 (m, 1H), 4.72 (ABq, J=13.6 Hz, Δδ=0.07, 2H), 5.11 (d, J=4.8Hz, 2H), 5.35 (d, J=5.7 Hz, 1H), 5.42 (d, J=5.1 Hz, 1H), 5.70 (d, J=2.6Hz, 1H), 5.74 (d, J=5.9 Hz, 1H), 7.42 (ddd, J=0.6, 4.8, 7.9 Hz, 1H),7.50 (ddd, J=0.7, 4.8, 7.9 Hz, 1H), 7.62 (dd, J=1.8, 8.3 Hz, 1H), 7.67(d, J=8.3 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 8.16 (tt, J=2.0, 8.6 Hz, 2H),8.66 ( dd, J=1.8, 4.8 Hz, 1H), 8.77 (dd, J=1.8, 4.8 Hz, 1H), 8.97 (dt,J=1.3, 9.2 Hz, 2H); IR (KBr) 3480, 3390, 3110, 2900, 1725, 1590, 1550,1475, 1420, 1390, 1360, 1340, 1285, 1175, 1140, 1090, 1050, and 1015cm⁻¹; mass spectrum [(+) FAB], m/z 722/724 (M+H)⁺, 744/746 (M+Na)⁺;Anal. Calcd. for C ₃₁H₃₂ClN₃O₁₅.1.5 H₂O: C, 49.71; H, 4.71; N, 5.61,Found: C, 49.68; H, 4.53; N, 5.59.

EXAMPLE 15(4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside

The title compound was prepared as a white glass (0.070 g, 10%) fromN-[2-chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetarride using aprocedure similar to Example 14, mp >85° C. (decomp.); ¹H NMR (DMSO-d₆)δ 3.07-3.14 (m, 1H), 3.14-3.23 (m, 1H), 3.25-3.36 (m, 2H₁), 3.36-3.47(m,.3H), 3.51-3.58 (m, 1H), 3.67-3.73 (m, 1H), 3.83-3.89 (m, 1H),4.29-4.34 (m, 2H), 4.54-4.62 (m, 2H), 4.79 (ABq, J=13.4 Hz, Δδ=0.17,2H), 5.05-5.08 (m, 2H), 5.31 (d, J=5.7 Hz, 1H), 5.34 (d, J=5.1 Hz, 1H),5.56 (d, J=6.4 Hz, 1H), 5.59 (d, J=3.1 Hz, 1H), 7.56 (ddd, J=0.9, 4.8,8.1 Hz, 1H), 7.71 (dd, J=2.0, 8.3 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 8.09(d, J=1.5 Hz, 1H), 8.33 (dt, J=1.8, 7.9 Hz, 1H), 8.81 (dd, J=1.8, 4.8Hz, 1H), 9.10 (dd, 3=0.7, 2.0 Hz, 1H); IR (KBr) 3390, 2910, 1730, 1625,1600, 1540, 1475, 1410, 1360, 1290, 1140, 1120, and 1040 cm⁻¹; massspectrum [(+) FAB], m/z 617/619 (M+H)⁺; Anal. Calcd. forC₂₅H₂₉ClN₂O₁₄.1.5 H₂O: C, 46.63; H, 5.01; N, 4.35, Found: C, 46.58; H,4.88; N, 4.26.

EXAMPLE 16N-[2-Chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)oxy]methyl]phenyl]-3-pyridinecarboxamide

Step 1

N-[2-Chloro-5-[[[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranoysl)-β-D-glucopyranosyl]oxy]methyl]phenyl]-3-pyridinecarboxamide

To a stirred solution of2-chloro-5-(hepta-O-acetyl-β-D-maltosyl-oxymethyl)-phenylamine (0.200 g,0.258 mmol) and triethylamine (0.119 mL, 0.851 mmol) in THF (3 mL) at 0°C. was added nicotinoyl chloride hydrochloride (0.0551 mg, 0.310 mmol).After 0.5 h at this temperature, it was warmed to rt and stirred anadditional 18 h. At this point, the solid was filtered off and washedwith additional THF (10 mL). The filtrate was then concentrated andtaken up in EtOAc (100 mL). This organic solution was washed with HO (10mL) and brine (10 mL) and then dried (Na₂SO₄). After concentration, theresidue was purified by preparatory plate chromatography (10:90MeOH:CHCl₃) to afford the product (0.183 g, 80%) as a white foam, mp83-86° C.; ¹H NMR (CDCl₃) δ 1.99 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H),2.03 (s, 3H), 2.04 (s, 3H), 2.10 (s, 3H), 2.16 (s, 3H), 3.67-3.72 (m,1H), 3.93-3.98 (m, 1H), 4.04 (dd, J=2.2, 11.9 Hz, 2H), 4.25 (dt, J=3.7,12.5 Hz, 2H), 4.53 (dd, J=2.9, 12.3 Hz, 1H), 4.60 (d, J=7.7 Hz, 1H),4.64 (d, J=12.5 Hz, 1H), 4.83-4.93 (m, 3H), 5.05 (t, J=10.1 Hz, 1H),5.23 (t, J=9.4 Hz, 1H), 5.34 (dd, J=9.7, 10.5 Hz, 1H), 5.41 (d, J=4.2Hz, 1H), 7.07 (dd, J=2.0 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.48 (ddd,J=0.9, 4.8, 7.9 Hz, 1H), 8.23 (ddd, J=1.5, 2.2, 7.9 Hz, 1H), 8.43 (s,1H), 8.48 (d, J=2.0 Hz, 1H), 8.82 (dd, J=1.5, 4.8 Hz, 1H), 9.15 (dd,J=0.7, 2.2 Hz, 1H); IR (KBr) 3400, 2950, 1755, 1675, 1600, 1550, 1420,1375, 1235, and 1050 cm⁻¹; mass spectrum [(+) FAB], m/z 881 (M+H)⁺, 903(M+Na)⁺; Anal. Calcd. for C₃₉H₄₅ClN₂O₁₉.2.0 H₂O: C, 51.07; H, 5.38; N,3.05, Found: C, 50.80; H, 4.83; N, 2.89.

Step 2

N-[2-Chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)oxy]methyl]phenyl]-3-pyridinecarboxamide

The title compound was prepared as a white foam (1.97 g, 57%) fromN-[2-chloro-5-[[[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranoysl)-β-D-glucopyranosyl]oxy]methyl]phenyl]-3-pyridinecarboxamideusing a procedure similar to step 2 of Example 9, mp >106° C. (decomp.);¹H NMR (DMSO-d₆) δ 3.02-3.13 (m, 2H), 3.19-3.29 (m, 2H), 3.31-3.39 (m,1H), 3.39-3.50 (m, 3H), 3.55-3.63 (m, 2H), 3.70-3.76 (m, 1H), 4.09 (q,J=5.3 Hz, 1H), 4.31 (d, J=7.9 Hz, 1H), 4.49-4.55 (m, 2H), 4.60 (d,J=12.5 Hz, 1H), 4.84-4.91 (m, 3H), 5.01 (d, J=3.7 Hz, 1H), 5.26 (d,J=5.1 Hz, 1H), 5.43 (d, J=6.4 Hz, 1H), 5.52 (d, J=3.1 Hz, 1H), 7.35 (dd,J=2.0, 8.3 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.56-7.60 (m, 2H), 8.31 (dt,J=2.0, 7.9 Hz, 1H), 8.77 (dd, J=1.5, 4.8 Hz, 1H), 9.12-9.14 (m, 1H),10.34 (s, 1H); IR (KBr) 3390, 2910, 2320, 1660, 1590, 1525, 1475, 1450,1420, 1360, 1310, 1190, 1140, 1080, and 1030 cm⁻¹; mass spectrum [(+)FAB], m/z 587 (M+H)⁺, 609 (M+Na)⁺; Anal. Calcd. for C25H₃₁ClN₂O₁₂.1.5HKO: C, 48.90; H, 5.58; N, 4.56, Found: C, 49.18; H, 5.52; N, 4.32.

EXAMPLE 17 Benzoic acid6-{4-chloro-3-[(pyridine-3-carbonyl)-amino]-benzyloxy}-4.5-dihydoxy-3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-ylmethylester hydrochloride

To a stirred solution of(R)-N-[5-[[[6-O-benzoyl4-O-[4,6-O-(phenylmethylene)-α-D-glucopyranosyl]-β-D-glucopyranosyl]oxy]methyl]-2-chlorophenyl]-3-pyridinecarboxamide(check other inyention record for preparation). (0.275 g, 0.353 mmol) inMeOH (10 mL) at 0° C. was added 1.0 M HCl in Et₂O (0.388 mL, 0.388mmol). After 10 min. at this temperature, it was warmed to rt andstirred an additional 15 min. The mixture was concentrated to a thin oiland then triturated with Et₂O (5 mL). At this point, the solid whichformed was filtered off and washed with additional Et₂O (4×, 2 mL). Thesolid was then dried on the high vacuum to afford the product (0.200 g,70%) as an off-white solid (86% pure, contaminated with 14% HCl salt ofSM), mp >157° C. (decomp.); ¹H NMR (DMSO-d₆) δ 3.09-3.19 (m, 2H), 3.24(dd, J=3.7, 9.4 Hz, 1H), 3.34-3.41 (m, 1H), 3.41-3.65 (m, 5H), 3.71 (dd,J=6.8, 8.1 Hz, 1H), 4.20-5.04 (m, 12H), 5.05 (d, J=3.7 Hz, 1H), 7.28(dd, J=2.0, 8.3 Hz, 1H), 7.46-7.55 (m, 4H), 7.60-7.66 (m, 1H), 7.82 (dd,J=5.1, 7.9 Hz, 1H), 7.94-7.99 (m, 2H), 8.58 (d, J=7.7 Hz, 1H), 8.90 (dd,J=1.5, 5.3 Hz, 1H), 9.23 (d, J=1.5 Hz, 1H), 10.54 (s, 1H); IR (KBr)3400, 2910, 2850, 2110, 1720, 1690, 1630, 1590, 1530, 1440, 1420, 1320,1275, 1120, 1070, 1050, 1025, and 715 cm⁻¹; mass spectrum [(+) ESI], m/z691.2 (M−HCl+H)⁺; Anal. Calcd. for C₃₂H₃₅ClN₂O₁₃.HCl.0.5 H₂O: C, 52.89;H, 5.06; N, 3.74, Found: C, 52.99; H, 5.27; N, 3.46.

EXAMPLE 18 (4-Chloro-3-nitro-benzyl)-1-deoxy-1-thio-β-D-maltoside

The title compound was prepared as a white solid from(4-chloro-3-nitro-benzyl)-hepta-O-acetyl-1-thio-β-D-maltoside using aprocedure similar to step 2 of Example 9, mp 90-93° C.; ¹H NMR (DMSO-d₆)δ 3.03-3.74 (m,, 11H), 3.80 (d, J=6.2 Hz, 1H), 3.86 (d, J=13.4 Hz, 1H),4.01-4.08 (m, 2H), 4.58 (bd, 2H), 4.98 (bd, 3H), 5.20-5.67 (bs, 3 H),7.65-7.72 (m, 2H), 8.03 (d, J=1.76 Hz, 1H).IR (KBr) 3400, 2930, 1550,1300 and 1075 cm⁻¹; mass spectrum [(−)FAB], m/z 526 (M−H)⁻; Anal. Calcd.for C₁₉H₂₆ClNO₁₂S.H₂O: C, 41.80; H, 5.13; N, 2.56, Found: C, 41.35; H,4.89; N, 2.40.

EXAMPLE 19 N-{2-Chloro-5-[β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamide

The title compound was prepared as a white solid fromN-{2-chloro-5-[hepta-O-acetyl-β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamideusing a procedure similar to step 2 of Example 9, mp 120-125° C.; ¹H NMR(CD₃OD-d₄) δ 2.17 (s, 3H), 3.23-3.33 (m, 3H), 3.41 (dd, J=9.9, 3.7, Hz,1H), 3.52-3.83 (m, 8H), 3.89 (dd, J=12.3, 2.0, Hz, 1H), 4.00 (d, J=13.2Hz, 1H), 4.20 (d, J=9.9 Hz, 1H), 5.15 (d, J=4.0 Hz, 1H), 7.20 (dd,J=8.4, 1.8, Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.74 (s, 1H); IR (KBr)3400, 2900, 1600, 1550 and 1050 cm⁻¹; mass spectrum [(−)FAB)], m/z 538(M−H)⁻; Anal. Calcd. for C₂₁H₃₀ClNO₁₁S 1.0 H₂O: C, 45.20; H, 5.78; N,2.51, Found: C, 45.43; H, 5.62; N, 2.43.

EXAMPLE 205-{[6,6′-Bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene

Step 1

5-[(β-Maltosyl)-oxy-methyl]-2-methyl-1-nitrobenzene

A stirred solution containing5-[(hepta-O-acetyl-β-maltosyl)-oxy-methyl]-2-methyl-1-nitrobenzene(prepared from 4-methyl-3-nitrobenzyl alcohol and acetobromomaltoseusing procedures similar to Example 1 ) (0.835 g, 1.06 mmol) and 25weight % NaOMe/MeOH (0.115 g, 0.531 mmol) in MeOH (25 mL) was refluxedfor 4 h. The reaction was cooled to ambient temperature and concentratedin vacuo. Purification by reverse phase BPLC (C18, 25% CH₃CN:H₂O) gave0.380 g (73%) of the title compound as a white foam; ¹H NMR (DMSO-d₆) δ2.50 (s, 3H), 3.60-3.21 (m, 2H), 3.22-3.57 (m, 7H), 3.59-3.65 (m, 2H),3.71-3.73 (m, 2H), 4.31 (d, 1H), 4.51-4.54 (m, 2H), 4.67 (d, 1H),4.87-4.91 (m, 3H), 5.02 (d, 1H), 5.29 (d, 1H), 5.44 (d, 1H), 5.53 (d,1H), 7.48 (d, 1H), 7.64 (dd, 1H), 8.01 (s, 1H).

Step 2

5-{[6,6′-Bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene

At 0° C., to a stirred solution of5-[(β-maltosyl)-oxy-methyl]-2-methyl-1-nitrobenzene (0.380 g, 0.774mmol) in pyridine (4.5 mL) was added portionwise a solution ofp-toluenesulfonyl chloride (0.812 g, 4.25 mmol) in CH₂Cl₂ (4.5 mL), overa period of 5 h. The reaction was quenched with H₂O (30 mnL) andextracted with EtOAc. The combined organic extracts were washedsuccessively with sat. aq. NaHCO3 (3×), with sat. aq. CuSO₄ (3×), withbrine (3×), dried (Na₂SO₄) and concentrated. Purification by preparativeHPLC (C18, 65% CH₂CN:H₂O) gave 0.373 g (59%) of the title compound as awhite solid, mp 85-92° C.; ¹H NMR (DMSO-d₆) δ 2.34 (s, 3H), 2.40 (s,3H), 2.48 (s, 3H), 3.01-3.10 (m, 2H), 3.12-3.17 (m, 1H), 3.23-3.40 (m,3H), 3.51-3.55 (m, 2H), 4.02-4.14 (m, 3H), 4.23-4.29 (m, 2H), 4.63 (ABq,J=13.1 Hz, Δδ=0.05, 2H), 4.92 (d, 1H), 5.01 (d, 1H), 5.22 (d, 1H), 5.36(d, 1H), 5.48 (d, 1H), 5.54 (d, 1H), 7.39 (d, 2H), 7.45-7.48 (m, 3H),7.60 (dd, 1H), 7.71-7.77 (m, 4H), 7.96 (s, 1H); IR (KBr) 3380, 2920,1600, 1530, 1360 and 1175 cm⁻¹; mass spectrum [(+) FAB], m/z 822(M+Na)⁺; Anal. Calcd. for C₃₄H₄₁NO₁₇S₂ H₂O: C, 49.93; H, 5.17; N, 1.75,Found: C, 49.77; H, 4.94; N, 1.70.

EXAMPLE 215-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene

At 0° C., to a stirred solution containing5-{[6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene(1.79 g, 2.24 mrmol), pyridine (5.43 mL, 67.1 mmol) and4-dimethylaminopyridine (1.25 g, 11.2 mmol) was added dropwise aceticanhydride (2.09 mL, 22.4 mmol). After 3 h, the reaction eventuallywarmed to room temperature. The solution was diluted with diethyl ether(100 mL), washed successively with H₂O (2×), sat. aq. NaHCO₃ (2×), sat.aq. CuSO₄ (2×), brine (2×), dried (NaSO₄) and concentrated. Purificationby flash chromatography (3, 4 and 5% MeOH:CHCl₃ gradient) gave 1.785 g,(79%), of the title compound as a white solid after crystallization fromEtOAc:hexane, mp 83° C.; ¹H NMR (DMSO-d₆) δ 1.910 (s, 3H), 1.918 (s,3H), 1.920 (s, 3H), 1.924 (s, 3H), 1.932 (s, 3H), 2.36 (s, 3H), 2.42 (s,3H), 2.51 (s, 3H), 3.66 (t; 1H), 3.86 (dd, 1H), 3.92-3.96 (m, 1H), 4.06(dd, 1H), 4.16-4.29 (m, 3H), 4.51-4.60 (m, 2H), 4.64-4.72 (m, 2H), 4.79(d, 1H), 4.89 (t, 1H), 5.06-5.13 (m, 2H), 5.24 (t, 1H), 7.43 (d, 2H),7.47-7.50 (m, 4H), 7.74-7.77 (m, 4H), 7.84 (s, 1H); mass spectrum [(+)FAB], m/z 1010 (M+H)⁺; Anal. Calcd. for C₄₄H₅₁NO₂₂S₂: C, 52.32; H, 5.09;N, 1.39, Found: C, 52.46; H, 5.15; N, 1.41.

EXAMPLE 225-{[6,6′-Dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene

At ambient temperature, to a stirred solution of 4-nitroimidazole (0.478g, 4.23 mmol) in DMF (8 mL) was added K₂CO₃ (0.278 g, 2.01 mmol). After0.5 h, to the reaction was added a solution of5-{[6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene(1.61 g, 0.201 mmol) in DMF (20 mL) and the reaction was heated at 100°C. for 24 h. The reaction was concentrated in vacuo. Purification byreverse phase HPLC (C18, 30% CH₃CN:H₂O) gave 0.40 g (29%) of the titlecompound as a white solid, mp 146° C.; ¹H NMR (DMSO-d₆) δ 2.48 (s, 3H),2.89 (t, 1H), 3.08 (t, 1H), 3.20-3.29 (m, 2H), 3.40-3.47 (m, 2H), 3.64(dt, 1H), 3.88 (dd, 1H), 3.974.03 (m, 2H), 4.21-4.27 (m, 2H), 4.43-4.47(m, 2H), 4.59 (d, 1H), 5.11 (d, 1H), 5.17 (d, 1H), 5.40 (br. s, 1H),5.57 (br. s, 1H), 5.68 (br. s, 1H), 5.84 (br. s, 1H), 7.41-7.46 (m, 2H),7.65 (d, 1H), 7.74 (d, 1H), 7.85 (s, 1H), 8.22 (d, 1H), 8.25 (d, 1H);mass spectrum [(+) FAB], m/z 682 (M+H)⁺; Anal. Calcd. for C₂₆H₃₁N₇O₁₅.2H₂O: C, 43.52; H, 4.92; N, 13.66, Found: C, 43.90; H, 4.72; N, 13.31.

EXAMPLE 235-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene

At ambient temperature, to a stirred solution of 4-nitroimidazole (0.177g, 1.57 mmol) in DMF (3 mL) was added K₂CO₃ (0.103 g, 0.747 mmol). After0.5 h, to the reaction was added a solution of5-{[2,2′,3,3′,4′-penta-O-acetyl-6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene(0.754 g, 0.747 mmol) in DMF (7 mL) and the reaction was heated at 100°C. for 4 h. At ambient temperature, the reaction was quenched with icecold H₂O (50 mL) and extracted with EtOAc. The organic extracts weredried (Na₂SO₄) and concentrated. Purification by flash chromatography(5, 6 and 7% MeOH:CHCl₃ gradient) gave 0.315 g, (47%), of the titlecompound as a white solid after crystallization from EtOAc:hexane, mp140° C.; ¹H NMR (DMSO-d₆) δ 1.92 (s, 3H), 1.93 (s, 3H), 1.94 (s, 6H),2.08 (s, 3H), 2.49 (s, 3H), 3.64 (dd, 1H), 3.91 (t, 1H), 4.00-4.06 (m,1H), 4.27-4.40 (m, 5H), 4.54 (d, 1H), 4.74-4.79 (m, 3H), 4.96 (dd, 1H),5.22-5.30 (m, 3H), 7.33 (dd, 1H), 7.43 (d, 1H), 7.69 (d, 1H), 7.72 (d,1H), 7.77 (d, 1H), 8.26 (d, 1H), 8.34 (d, 1H); mass spectrum [(+) FAB],m/z 892 (M+H)⁺; Anal. Calcd. for C₃₆H₄₁N₇O₂₀: C, 48.49; H, 4.63; N,11.00, Found: C, 48.32; H, 4.52; N, 10.90.

1. A compound of formula I having the structure

wherein R¹, R², R³, R⁴, and R⁵ are each, independently, hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R⁸; R⁶ and R⁷ are each, independently, —OH, —OR⁹, O-tert-butyldimethylsilyl, O-trialkylsilyl of 1-6 carbon atoms per alkyl moiety, O-triphenylsilyl,

R⁸, R¹⁰, R¹¹, and R¹² are each, independently, hydrogen, —CN, —NO₂, halogen, CF₃, alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy of 1-6 carbon atoms; R⁹ is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R⁸; Y is S, NH, NMe, or CH₂; W is halogen, —CN, CF₃, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon atoms, or phenyl mono-, di-, or tri-substituted with R⁸; Z is —NO₂, —NH₂, —NHR¹³, or —NHCO-Het; R¹³ is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, benzoyl in which the phenyl moiety is substituted with R⁸, or R¹³ is an α-amino acid in which the a carboxyl group forms an amide with the nitrogen of Z, wherein if said amino acid is glutarnic acid or aspartic acid, the non-α carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms; Het is pyridyl substituted with R⁸, thienyl substituted with R⁸, furyl substituted with R⁸, oxazolyl substituted with R⁸, pyrazinyl substituted with R⁸, pyrimidinyl substituted with R⁸, or thiazolyl substituted with R⁸; R¹⁴ is R⁸, —NH₂, —CO₂H, or —NH-acyl of 2-7 carbon atoms; n=0-3; or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein R¹, R², R³, R⁴, and R⁵ are each, independently, hydrogen or acyl of 2-7 carbon; R⁶ and R⁷ are each, independently, —OH, —OR⁹, O-tert-butyldimethylsilyl,

R⁹ is acyl of 2-7 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R⁸; Y is S; and R¹³ is acyl of 2-7 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R⁸, or R¹³ is an α-amino acid in which the a carboxyl group forms an amide with the nitrogen of Z, wherein if said amino acid is glutamic acid or aspartic acid, the non-α carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms.
 3. The compound of claim 1 which is: e) (4-Chloro-3-nitro-benzyl)-hepta-O-acetyl-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof; f) (3-Amino-4-chloro-benzyl) hepta-O-acetyl-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof; g) N-{2-chloro-5-[hepta-O-acetyl-β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamide or a pharmaceutically acceptable salt thereof; r) (4-Chloro-3-nitro-benzyl)-1-deoxy-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof; or s) N-{2-chloro-5-[β-D-maltosyl-1-thio)-methyl]-phenyl}-acetamide or a pharmaceutically acceptable salt thereof.
 4. (canceled)
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. A pharmaceutical composition which comprises a compound of formula I having the structure

wherein R¹, R², R³, R⁴, and R⁵ are each, independently, hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R⁸; R⁶ and R⁷ are each, independently, —OH, —OR⁹, O-tert-butyldimethylsilyl, O-trialkylsilyl of 1-6 carbon atoms per alkyl moiety, O-triphenylsilyl,

R⁸, R¹⁰, R¹¹, and R¹² are each, independently, hydrogen, —CN, —NO₂, halogen, CF₃, alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy of 1-6 carbon atoms; R⁹ is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R⁸; Y is S, NH, NMe, or CH₂; W is halogen, —CN, CF₃, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon atoms, or phenyl mono-, di-, or tri-substituted with R⁸; Z is —NO₂, —NH₂, —NHR¹³, or —NHCO-Het; R¹³ is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, benzoyl in which the phenyl moiety is substituted with R⁸, or R¹³ is an α-amino acid in which the a carboxyl group forms an amide with the nitrogen of Z, wherein if said amino acid is glutamic acid or aspartic acid, the non-α carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms; Het is pyridyl substituted with R⁸, thienyl substituted with R⁸, furyl substituted with R⁸, oxazolyl substituted with R⁸, pyrazinyl substituted with R⁸, pyrimidinyl substituted with R⁸, or thiazolyl substituted with R⁸; R¹⁴ is R⁸, —NH₂, —CO₂H, or —NH-acyl of 2-7 carbon atoms; n=0-3; or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.
 9. A compound selected from the group consisting of: N-{5-[(Hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}-L-aspartamide-γ-tert-butyl ester or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[(2,2′,3,3′,4′,6,6′)-hepta-O-acetyl-β-D-maltosyl-oxymethyl]-phenyl}- (9H-fluoren-9-ylmethoxycarbonyl)-L-alaninamide or a pharmaceutically acceptable salt thereof; 4-Benzoyl-N-{2-chloro-5-[(2,2′,3,3′,4′,6,6′-hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-phenyl}-benzamide or a pharmaceutically acceptable salt thereof; N-[2-Chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetamide or a pharmaceutically acceptable salt thereof; N-{5-[6,6′-Di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-2-methyl-phenyl}-acetamide or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[6,6′-di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-phenyl}-acetamide or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[([6,6′-di-O-benzoyl-β-D-maltosyl]oxy)methyl]phenyl}-acetamide or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[([6,6′-di-O-benzoyl-2,2′,3,3′,4′-penta-acetyl-β-D-maltosyl]oxy)-methyl]phenyl}-acetamide or a pharmaceutically acceptable salt thereof; (4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside-6-(3-pyridinecarboxylate) or a pharmaceutically acceptable salt thereof; (4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof; N-[2-Chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)oxy]methyl]phenyl]-3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof, Benzoic acid 6-{4-chloro-3-[(pyridine-3-carbonyl)-amino]-benzyloxy}-4,5-dihydoxy-3- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-ylmethyl ester or a pharmaceutically acceptable salt thereof; 5-{[6,6′-Bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; 5-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; 5-{[6,6′-Dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; and 5-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof.
 10. A pharmaceutical composition which comprises a compound selected from the group consisting of: N-{5-[(Hepta-O-acetyl-β-D-maltosyloxy)-methyl]-2-chloro-phenyl}-L-aspartamide-γ-tert-butyl ester or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[(2,2′,3,3′,4′,6,6′)-hepta-O-acetyl-β-D-maltosyl-oxymethyl]-phenyl}- (9H-fluoren-9-ylmethoxycarbonyl)-L-alaninamide or a pharmaceutically acceptable salt thereof; 4-Benzoyl-N-{2-chloro-5-[(2,2′,3,3′,4′,6,6′-hepta-O-acetyl-β-D-maltosyl)-oxy-methyl]-phenyl}-benzamide or a pharmaceutically acceptable salt thereof; N-[2-Chloro-5-(β-D-maltosyl-oxymethyl)-phenyl]-acetamide or a pharmaceutically acceptable salt thereof; N-{5-[6,6′-Di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-2-methyl-phenyl}-acetamide or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[6,6′-di-O-(tert-butyl-dimethyl-silyl)-β-D-maltosyloxy-methyl]-phenyl}-acetamide or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[([6,6′-di-O-benzoyl-β-D-maltosyl]oxy)methyl]phenyl}-acetamide or a pharmaceutically acceptable salt thereof; N-{2-Chloro-5-[([6,6′-di-O-benzoyl-2,2′,3,3′,4′-penta-acetyl-β-D-maltosyl]oxy)-methyl]phenyl}-acetamide or a pharmaceutically acceptable salt thereof; (4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside-6-(3-pyridinecarboxylate) or a pharmaceutically acceptable salt thereof; (4-Chloro-3-nitrophenyl)methyl-4-O-[6-O-(3-pyridinylcarbonyl)-α-D-glucopyranosyl]-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof; N-[2-Chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)oxy]methyl]phenyl]-3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof; Benzoic acid 6-{4-chloro-3-[(pyridine-3-carbonyl)-amino]-benzyloxy}-4,5-dihydoxy-3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2- ylmethyl ester or a pharmaceutically acceptable salt thereof; 5-{[6,6′-Bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; 5-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-bis-O-(4-toluenesulfonyl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; 5-{[6,6′-Dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; and 5-{[2,2′,3,3′,4′-Penta-O-acetyl-6,6′-dideoxy-6,6′-bis(4-nitro-imidazol-1-yl)-β-maltosyl]-oxy-methyl}-2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 